Abstract
Ferulic acid-related compounds possess antioxidant activity. Dehydrodiisoeugenol and ferulic acid dimer (bis-FA), but not the parent monomers isoeugenol and ferulic acid, inhibit lipopolysaccharide (LPS)-induced cyclooxygenase-2 (COX-2) gene expression in RAW 264.7 cells. To clarify the mechanism of their inhibitory effects on COX-2 expression, the phenolic O-H bond dissociation enthalpy (BDE) and ionization potential (IP) of 8 ferulic acid-related compounds were calculated by both semi-empirical molecular orbital (AM1, PM3) and ab initio (3-21G* 6-31G*) and density function theory (DFT) (B3LYP) methods. COX-2 inhibition appeared in compounds with phenolic O-H BDE higher than 85.76 kcal/mol, as calculated by the density function theory (DFT) approach. The phenolic O-H BDEs of the most potent compounds, dehydrodiisoeugenol and bis-FA, were 85.99 and 85.76 kcal/mol, respectively. No causal relationship between COX-2 inhibition and IP was found. Neither dehydrodiisoeugenol nor bis-FA possessed significant scavenging activity against the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical. The NSAID-like activity of dehydrodiisoeugenol and bis-FA appears to be related to their phenol function. Binding of activator protein-1 (AP-1) to the 12-tetradecanoylphorbol-13-acetate-responsive element (TRE) sequence in LPS-stimulated cells was inhibited by bis-FA at 1 microM and dehydrodiisoeugenol at 0.1 microM, but not by the parent monomers isoeugenol and ferulic acid.
Publication types
-
Comparative Study
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
-
Antioxidants / pharmacology*
-
Biphenyl Compounds / pharmacology
-
Bridged Bicyclo Compounds, Heterocyclic / chemistry
-
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
-
Cell Line
-
Coumaric Acids / chemistry
-
Coumaric Acids / pharmacology*
-
Cyclooxygenase 2 Inhibitors / metabolism*
-
Dimerization
-
Electrophoretic Mobility Shift Assay
-
Eugenol / analogs & derivatives*
-
Eugenol / chemistry*
-
Eugenol / pharmacology*
-
Free Radical Scavengers / pharmacology
-
Gene Expression Regulation / drug effects
-
Guaiacol / analogs & derivatives
-
Guaiacol / chemistry
-
Guaiacol / pharmacology
-
Hydrazines / pharmacology
-
Lipopolysaccharides / pharmacology
-
Macrophages / drug effects
-
Macrophages / enzymology*
-
Mice
-
Models, Chemical
-
Models, Theoretical
-
Phenol / chemistry*
-
Picrates
-
Structure-Activity Relationship
-
Tetradecanoylphorbol Acetate / chemistry
-
Tetradecanoylphorbol Acetate / metabolism
-
Thermodynamics
-
Transcription Factor AP-1 / antagonists & inhibitors*
-
Transcription Factor AP-1 / metabolism
Substances
-
4,8-bis(4-hydroxy-3-methoxyphenyl)-3,7-dioxabicyclo(3.3.0)octane-2,6-dione
-
Anti-Inflammatory Agents, Non-Steroidal
-
Antioxidants
-
Biphenyl Compounds
-
Bridged Bicyclo Compounds, Heterocyclic
-
Coumaric Acids
-
Cyclooxygenase 2 Inhibitors
-
Free Radical Scavengers
-
Hydrazines
-
Lipopolysaccharides
-
Picrates
-
Transcription Factor AP-1
-
dehydrodiisoeugenol
-
Phenol
-
Eugenol
-
isoeugenol
-
Guaiacol
-
ferulic acid
-
1,1-diphenyl-2-picrylhydrazyl
-
Tetradecanoylphorbol Acetate